B lymphopoiesis occurs in both fetal and adult life, but the patterns of development, the response of precursors to B lymphopoietic growth factors, and properties of the B cells generated differ. The aim of this proposal is to identify B cell progenitors that emerge during embryogenesis and test the hypothesis that some of them persist into adult life where they contribute to postnatal immunity. Studies in aim 1 will investigate whether the developmental potential and cytokine responsiveness of phenotypically defined fetal B cell progenitor subpopulations are distinct from that of pro-B cells in postnatal bone marrow. A particular focus of these studies will be on a newly identified B220 (CD45R)-CD19+ fetal liver progenitor. These cells can generate macrophages and B cells that have characteristics that suggest they are B-1 B cells, such as co- expression of surface IgM, CD1 lb (Mac-l), and/or CD5. CD45R-CD19+ cells, which include a bipotential B/macrophage progenitor, are also present in adult bone marrow and can generate progeny with B-1 B cell characteristics. Various in vitro and in vivo approaches wilt be used in aim 2 to test the hypothesis that they are a self-renewing reservoir of fetal-derived B/macrophage progenitors that persist into postnatal life. The final series of experiments in aim 3 will examine the contribution of macrophages and B cells derived from the fetal and adult progenitors defined in aims 1 and 2 to the postnatal immune system. These studies will further characterize fetal B lymphopoiesis and are relevant to understanding the nature of B lymphoid progenitors in cord blood, which is being increasingly used as a source of hematopoietic donor cells. The data also have implications for understanding the origin of tumors with B/macrophage characteristics.